CN107428776A - Manufacture the 4,5,6,7 tetrahydrochysene isoxazoles simultaneously alcohol of [5,4 c] pyridine 3 - Google Patents
Manufacture the 4,5,6,7 tetrahydrochysene isoxazoles simultaneously alcohol of [5,4 c] pyridine 3 Download PDFInfo
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- CN107428776A CN107428776A CN201680017239.7A CN201680017239A CN107428776A CN 107428776 A CN107428776 A CN 107428776A CN 201680017239 A CN201680017239 A CN 201680017239A CN 107428776 A CN107428776 A CN 107428776A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Abstract
The present invention relates to a kind of method for being used for 4,5,6,7 tetrahydrochysene isoxazoles of being abbreviated as THIP simultaneously [5,4 c] pyridine 3 alcohol of the synthesis with INN title Gaboxadols since the ketone of pyrrolidines 2.This method includes obtaining the new straight-forward procedure of the dimethyl dicarboxylate of 5 hydroxyl of intermediate, 3,6 dihydropyridine 1,4 (2H) 5 or 5 hydroxyl of intermediate 3,6 dihydropyridine 1,4 (2H) diethyl dicarboxylate.
Description
Invention field
Being used for the synthesis since pyrrolidin-2-one the present invention relates to one kind has INN titles Gaboxadol (gaboxadol)
The 4,5,6,7- tetrahydrochysene isoxazoles for being abbreviated as THIP simultaneously [5,4-c] pyridine -3- alcohol method.This method includes obtaining intermediate
(the 2H)-dimethyl dicarboxylate of 5- hydroxyl -3,6- dihydropyridines -1,4 or intermediate 5- hydroxyl -3,6- dihydropyridines -1,4 (2H) -
The new straight-forward procedure of diethyl dicarboxylate.
Background technology
The compound 4,5,6,7- tetrahydrochysene isoxazoles for being abbreviated as THIP with INN title Gaboxadols simultaneously [5,4-c] pyrrole
Pyridine -3- alcohol is disclosed and has following described molecular structure first in the EP patent No.s 0000338.
Gaboxadol is for the GABA containing δAAcceptor has the GABA of functionally selectiveAReceptor stimulating agent.It has been proposed that
Gaboxadol is used to treat various nerves and phrenoblabia, such as epilepsy, Parkinson's, schizophrenia and Huntington chorea
Disease.WO 97/02813 discloses the purposes that Gaboxadol is used to treat sleep-disorder, and in the preclinical models of depression
Obtain positive findings (WO 2004/112786).
Gaboxadol can be prepared using method well known in the art.EP 0000338 and Krogsgaard-Larsen,
Acta Chem.Scand.B [Scandinavia chemistry journal B], (1977), 31:584-588 discloses wherein Gaboxadol
The method prepared by ethyl -1- benzyl -3- oxo-piperidine -4- carboxylates.Rong and Chang, Chin.J.Med.Chem. [China
Pharmaceutical chemistry magazine] (2007), 17:166-169 discloses to be made since glycine ester hydrochloride, benzyl chloride and gamma-butyrolacton
The method for making Gaboxadol.WO 2005/023820 disclose from 3, N- dihydroxy-Pyrazinamide as parent material in
The mesosome isoxazole method that simultaneously [5,4-c] pyridine -3- alcohol (HIP) manufactures Gaboxadol.
On parameter such as plant-scale cost benefit, security, robustness and applicability, ripple is added to current
Needs be present in the superior alternative solution of the manufacture method of husky.
The content of the invention
The present invention's the inventors have found that a kind of new method for being used to synthesize Gaboxadol, this method include obtaining
Obtain the direct of (the 2H)-dimethyl dicarboxylate of key intermediate 5- hydroxyl -3,6- dihydropyridines -1,4 in Gaboxadol synthesis
Process.This method, which is this have the advantage that since parent material that is cheap and being easily obtained, has good Atom economy
The cost-benefit commercial run of (avoiding using huge blocking group).Another advantage of this method is that this method is applied to
Industrial expansion scale.
In one embodiment, it is used to manufacture Gaboxadol or for manufacturing the change with lower Formula IV the present invention relates to a kind of
The method of compound,
Both wherein R1 and R2 are methyl or ethyl, be the described method comprises the following steps：
A) compound with Formulas I is made,
Reacted with anhydrous acid and methanol or ethanol, to obtain the compound with Formula II,
Wherein when applying methanol in the reaction, R2 is methyl, and when applying ethanol in the reaction, R2 is second
Base.
In another embodiment, it is used to manufacture Gaboxadol or for manufacturing with lower Formula IV the present invention relates to a kind of
The method of compound,
Both wherein R1 and R2 are methyl or ethyl, be the described method comprises the following steps：
B) compound with Formula II is made
Reacted with alkali and glyoxalic acid methylester or glyoxylic acid ethyl ester, to obtain the compound with formula III,
C) compound with formula III is changed into the compound with formula IV by hydrogenating
D) make that there is the compound of formula IV to be reacted with methylchloroformate or ethyl chloroformate, to obtain with Formula V
Compound
Wherein when applying methylchloroformate in the reaction, R1 is methyl, or ought apply chloro-carbonic acid in the reaction
During ethyl ester, R1 is ethyl, and
Wherein R2 independently represents methyl or ethyl, and
Wherein when applying glyoxalic acid methylester in the reaction, R3 is methyl, or ought apply glyoxalic acid in the reaction
During ethyl ester, R3 is ethyl.
In another embodiment, it is used to manufacture Gaboxadol or for manufacturing with lower Formula IV the present invention relates to a kind of
The method of compound,
It the described method comprises the following steps：
E) make this that there is the compound of Formula V
Reacted with the caustic alcohol in the sodium methoxide or ethanol in methanol, to obtain the compound with Formula IV,
R1, R2 and R3 of the wherein compound with Formula V independently represent methyl or ethyl, and wherein when in the reaction
During middle sodium methoxide using in methanol, have Formula IV compound R1 and R2 both be all methyl, or ought be in the reaction
During using caustic alcohol in ethanol, have Formula IV compound R1 and R2 both be all ethyl.
In one embodiment, it is used to manufacture Gaboxadol or for manufacturing the chemical combination with Formula IV the present invention relates to a kind of
The method of thing, methods described include all method and step a) presented above, b), c), d) and e).
Definition
Throughout the specification, term " Gaboxadol " is intended to any form for including the compound, such as free alkali (two
Property ion) and pharmaceutically acceptable salt.The amphion and pharmaceutically acceptable salt include anhydride and solvate such as
Hydrate.Free alkali and salt and its anhydride and solvate include amorphous and crystal form.In a particular embodiment, ripple is added
Husky in the form of monohydrate.In another specific embodiment, Gaboxadol or its pharmaceutically acceptable salt are crystallizations
, such as crystalline hydrochloride, crystalline hydrobromic acid salt or crystallization amphion monohydrate.
With embodiment
The purpose of the present invention is to find a kind of sane, safe and cost-benefit method for being used to synthesize Gaboxadol.
The present invention's the inventors have found that obtain carbamate intermediate (the compound VI in following scheme I)
Direct method, the intermediate be Gaboxadol synthesis in key intermediate.This method is from starting that is cheap and being readily available
Material pyrrolidin-2-one starts.Compared with the method disclosed in the prior art, method of the invention is this have the advantage that with good
Good Atom economy, because intermediate 5- hydroxyls -3,6- dihydropyridine-Isosorbide-5-Nitrae (2H)-dimethyl dicarboxylate directly obtains, no
Need to use N- benzyl protecting groups.
In short, synthesis is described in following scheme I.
Scheme I
R1, R2 and R3 independently represent methyl or ethyl.
First step including the use of anhydrous acid methanol or ethanol makes pyrrolidin-2-one (compound I) while open loop and ester
Change, the compound with Formula II of separation to provide as solid.By using anhydrous acid, the party in compound I open loop
This part of method is carried out in anhydrous conditions, and this produces compound II with good yield.In one embodiment, the anhydrous acid
It is methanesulfonic acid.In another embodiment, open loop is carried out in one-pot synthesis, there is provided compound II mesylate,
It is portrayed as following compound IIb.
Subsequent step (compound II to V) is continuously without separation of intermediates.First, compound II and glyoxalic acid first are made
Ester or glyoxylic acid ethyl ester react in the presence of base in non-polar solven, to form imines (compound III).In an implementation
In example, the alkali is potassium carbonate.In a preferred embodiment, the alkali is triethylamine.In one embodiment, it is described nonpolar
Solvent is heptane.In a preferred embodiment, the non-polar solven is toluene.In one embodiment, three second of the reaction
Amine is carried out, and ionic liquid solution is formed in situ in the form of methanesulfonic acid triethyl ammonium.Methanesulfonic acid triethyl ammonium absorbs all
Water, and react can continue without extra dehydrating agent.In addition, ionic liquid and water form single layer,
It can be separated at the end of reaction with the layer containing product.
Compound III for example changes into compound IV by catalytic hydrogenation by using palladium charcoal.
Compound IV is set to be reacted with methylchloroformate or ethyl chloroformate, to form the chemical combination as the intermediate of this method
Thing V.Compound V can be by using acidifying water washing, be purified by distillation or by the combination of both purification strategies.One
In individual embodiment, compound V is purified by thin-film distillation, to obtain the compound V in colorless oil.
Compound VI is converted compound V to by closed loop (diekmann condensation) by adding sodium methoxide or caustic alcohol, with
Produce compound VI.The condition applied in diekmann condensation with high yield provide compound VI, and avoid the formation of it is excessive with
The undesirable compound of lower description.
Compound VI (ketoenol tautomerization) can exist in the form of enol or its ketone.As ketone, it can be with methylene glycol
Or ethylene glycol (preferably ethylene glycol) reaction is ketal protected to be formed, there is provided compound VII.
Compound VII is then changed into hydroxamic acid (compound VIII) with azanol.Using compound VIII as solid
Separation.
Gaboxadol (compound IX) is synthesized by compound VIII and has been described in EP 0000338 and Krogsgaard-
Larsen, Scandinavia chemistry journal B, 1977,31:In 584-588.
According to the embodiment of the present invention
Embodiments of the invention are disclosed below.First embodiment is expressed as E1, and second embodiment is expressed as E2, etc.
Deng.
E1. a kind of method for being used to manufacture the compound with lower Formula IV,
Both wherein R1 and R2 are methyl or ethyl, be the described method comprises the following steps：
A) compound with Formulas I is made,
Reacted with anhydrous acid and methanol or ethanol, to obtain the compound with Formula II,
Wherein when applying methanol in the reaction, R2 is methyl, and when applying ethanol in the reaction, R2 is second
Base.
E2. the method according to embodiment 1, wherein the anhydrous acid is anhydrous methanesulfonic acid.
E3. the method according to embodiment 2, wherein the compound with Formula II is as the methanesulfonic acid for being portrayed as Formula II b
Salt obtains
Wherein when applying methanol in the reaction, R2 is methyl, and when applying ethanol in the reaction, R2 is second
Base.
E4. the method according to embodiment 3, wherein the compound with Formula II b is obtained by one-pot synthesis.
E5. the method according to any one of embodiment 1-4, methods described include additionally below the step of：
B) make this that there is Formula II or IIb compound
Reacted with alkali and glyoxalic acid methylester or glyoxylic acid ethyl ester, to obtain the compound with formula III,
C) compound with formula III is changed into the compound with formula IV by hydrogenating
D) make that there is the compound of formula IV to be reacted with methylchloroformate or ethyl chloroformate, there should be Formula V to obtain
Compound
Wherein when applying methylchloroformate in the reaction, R1 is methyl, or ought apply chloro-carbonic acid in the reaction
During ethyl ester, R1 is ethyl, and
Wherein when applying methanol in the reaction, R2 is methyl, or when applying ethanol in the reaction, R2 is second
Base, and
Wherein when applying glyoxalic acid methylester in the reaction, R3 is methyl, or ought apply glyoxalic acid in the reaction
During ethyl ester, R3 is ethyl.
E6. the method according to embodiment 5, wherein step a), b), c) and d) carried out in toluene.
E7. a kind of method for being used to manufacture the compound with lower Formula IV,
Both wherein R1 and R2 are methyl or ethyl, be the described method comprises the following steps：
B) make that there is Formula II or IIb compound
Reacted with alkali and glyoxalic acid methylester or glyoxylic acid ethyl ester, to obtain the compound with formula III,
C) compound with formula III is changed into the compound with formula IV by hydrogenating
D) make that there is the compound of formula IV to be reacted with methylchloroformate or ethyl chloroformate, there should be Formula V to obtain
Compound
Wherein when applying methylchloroformate in the reaction, R1 is methyl, or ought apply chloro-carbonic acid in the reaction
During ethyl ester, R1 is ethyl, and
Wherein R2 independently represents methyl or ethyl, and
Wherein when applying glyoxalic acid methylester in the reaction, R3 is methyl, or ought apply glyoxalic acid in the reaction
During ethyl ester, R3 is ethyl.
E8. the method according to embodiment 7, wherein step b), c) and d) carried out in toluene.
E9. the method according to any one of embodiment 5-8, wherein the alkali used in step b) is triethylamine.
E10. the method according to any one of embodiment 5-9, wherein the compound with Formula V is washed by using acidifying
Wash or purified by distillation or by the combination of both purification strategies.
E11. the method according to any one of embodiment 5-10, wherein the compound with Formula V passes through thin-film distillation
Purifying.
E12. the method according to any one of embodiment 1-11, methods described include additionally below the step of：
E) make this that there is the compound of Formula V
Reacted with the caustic alcohol in the sodium methoxide or ethanol in methanol, to obtain the compound with Formula IV,
R1, R2 and R3 of the wherein compound with Formula V independently represent methyl or ethyl, and
When applying the sodium methoxide in methanol in the reaction, both the R1 and R2 of the compound with Formula IV are first
Base, or when applying the caustic alcohol in ethanol in the reaction, both the R1 and R2 of the compound with Formula IV are ethyl.
E13. a kind of method for being used to manufacture the compound with lower Formula IV,
It the described method comprises the following steps：
E) compound with Formula V is made
Reacted with the caustic alcohol in the sodium methoxide or ethanol in methanol, to obtain the compound with Formula IV,
R1, R2 and R3 of the wherein compound with Formula V independently represent methyl or ethyl, and wherein
When applying the sodium methoxide in methanol in the reaction, both the R1 and R2 of the compound with Formula IV are first
Base, or when applying the caustic alcohol in ethanol in the reaction, both the R1 and R2 of the compound with Formula IV are ethyl.
E14. the method according to any one of embodiment 12-13, wherein step e) are carried out in toluene, preferably 2-6
The toluene of volume, such as the toluene of the toluene of 3-5 volumes, e.g., from about 4 volumes.
E15. the reaction in the method according to any one of embodiment 12-14, wherein step e) is in 70 DEG C and 85 DEG C
At a temperature of between carry out.
E16. the reaction in the method according to any one of embodiment 12-15, wherein step e) is at a reflux temperature
Carry out.
E17. a kind of method for being used to manufacture the compound with Formula IV, methods described include appointing according in embodiment 1-16
All step a) described in one, b), c), d) and e).
E18. the method according to any one of embodiment 1-17, wherein the compound with Formula IV is subsequently converted to
Compound with Formula IX,
It is Gaboxadol that this, which has the compound of Formula IX,.
E19. a kind of method for manufacturing Gaboxadol, wherein compound VI are the intermediates of methods described, and its
Described in compound VI be to be manufactured by the method according to any one of embodiment 1-17.
E20. a kind of method for manufacturing Gaboxadol, methods described are included by according to any one of embodiment 1-17
Described compound of the method manufacture with Formula IV, and Jia Bosha is then manufactured by the compound with Formula IV
Piece.
E21. the method according to any one of embodiment 18-20, methods described include wherein making the change with Formula IV
The step of compound and glycol reaction are to obtain the compound with Formula VII,
Both wherein R1 and R2 are methyl or ethyl.
E22. the method according to any one of embodiment 18-21, methods described include wherein making the change with Formula VII
The step of compound and azanol reaction are to obtain the compound with Formula VIII
Wherein R1 represents methyl or ethyl.
E23. the method according to any one of embodiment 18-22, methods described are included wherein by with Formula VIII
Compound is converted into the step of compound with Formula IX,
It is Gaboxadol that this, which has the compound of Formula IX,.
E24. there is the compound of lower Formula IV,
Both wherein R1 and R2 are methyl or ethyl, and the compound passes through the side according to any one of embodiment 1-17
Method obtains.
E25. there is the compound of Formula IX,
The compound is Gaboxadol, is obtained by the method according to any one of embodiment 1-23.
E26. a kind of compound with Formula V,
Wherein R1, R2 and R3 are entirely methyl.
E27. a kind of compound with Formula II b,
Wherein R2 is methyl or ethyl.
All references (including publication, patent application and patent) are complete with its by quoting
Text is combined hereby, and the degree quoted individually and is explicitly indicated and is incorporated by reference simultaneously such as each bibliography
And illustrated herein with its full text (to it is allowed by law at utmost), the specific file made but regardless of elsewhere herein
Any combination being provided separately.
Unless instruction or otherwise clearly contradicted in addition herein, otherwise in the description of the invention in the context, term " one
The use of individual/kind of (a/an) " and " being somebody's turn to do (the) " and similar referent should be interpreted that including both odd number and plural number.
It is unless otherwise stated or otherwise clearly contradicted, otherwise herein using being related to the term of one or more key elements such as
This hair of " including (comprising) ", " having (having) ", " including (including) " or " containing (containing) "
The description of bright any aspect or aspect is aimed to provide to " being made up of that one or more specific factor ", " substantially by that
Kind or a variety of specific factors composition " or the similar aspect of the invention or side of " basically comprising that one or more specific factor "
The support in face is (for example, unless otherwise stated or otherwise clearly contradicted, the method for being otherwise described herein as including specific factor
It is interpreted as also describing the composition being made up of that key element).
It should be understood that many aspects of the invention, embodiment, embodiment and the feature that are mentioned herein can be independent
Ground is claimed with any combinations.
The present invention will be illustrated by following non-limiting examples.
Example
Example 1：
Synthesize 4-Aminobutanoicacid ethyl ester, mesylate (compound IIb).
Reactor is equipped with pyrrolidin-2-one (400kg), toluene (1044kg) and ethanol (316kg) at room temperature.To this
Anhydrous methanesulfonic acid (492Kg) is added in solution.Heat the mixture to T=110 DEG C -115 DEG C, P=1.5-2 bars, and stirring
It is lower to be kept for 22 hours.Then the mixture is cooled to T=60 DEG C -65 DEG C, and then diluted it with toluene (696kg).
Suspension is cooled to T=50 DEG C -55 DEG C and kept for 1 hour under agitation, and was then cooled further in 1.5 hours
T=20 DEG C -30 DEG C.The suspension is maintained 1 hour under agitation, then by solid by centrifuging and being washed with toluene.
Wet solid is dried 2 hours at T=45 DEG C -50 DEG C under vacuo, and then dried 15 hours at T=50 DEG C -55 DEG C,
Produce 1062Kg 4-Aminobutanoicacid ethyl ester, mesylate.
Example 2：
The program described in example 1 is repeated, produces 1059kg 4-Aminobutanoicacid ethyl ester, mesylate.
Example 3：
Synthesize 4- ((2- ethyoxyl -2- oxoethyls (methoxycarbonyl) amino) ethyl butyrates (compound V).
Under a nitrogen at room temperature by reactor equipped with 4-Aminobutanoicacid ethyl ester mesylate (616kg), toluene
50% glyoxylic acid ethyl ester (500kg) in (2088kg) and toluene.Suspension is cooled to T=-2 DEG C.Added in 90 minutes
Triethylamine (275kg), is maintained the temperature in the range of -2 DEG C -2 DEG C.Stir the mixture for 2.5 hours and then use toluene
(522kg) dilutes.The upper strata of (E) -4- ((2- ethyoxyl -2- oxos ethylidene) amino) ethyl butyrate will be contained at T=0 DEG C
Separate and be transferred in autoclave.In anhydrous sodium sulfate (100kg) and Pd/C 10% (18kg is as moist catalysis) presence
Under, solution is hydrogenated under T=10 DEG C -15 DEG C and 1.0-1.5 bars of Hydrogen Vapor Pressure.When absorption of hydrogen is completed, by mixture
It is heated to T=15 DEG C -20 DEG C and is diluted with water (700L), is maintained the temperature in the range of T=20 DEG C -25 DEG C.Filtered out by crossing
Remove catalyst.Filter is washed with toluene (348kg).Whole solution is transferred to another and contains potassium carbonate (360kg)
In reactor.Mixture is cooled to T=-5 DEG C -0 DEG C.Methylchloroformate (226kg) was added in 8 hours, maintains temperature in T
In the range of=- 5 DEG C -2 DEG C.Then mixture is handled into simultaneously stir about 2 hours at T=0 DEG C -5 DEG C with water (600L), and
It is then heated to 40 DEG C -45 DEG C.By water layer separate and at T=40 DEG C -45 DEG C with water (1200L), watery hydrochloric acid (HCl 11%,
521kg) and then washed with water (3x500L), pH to 7 will be adjusted with potassium carbonate in last washing.It is dense by being evaporated under reduced pressure
Contracted the organic solution, and 4- ((2- ethyoxyl -2- oxoethyls) (methoxycarbonyl) amino) ethyl butyrate for producing 425kg (is surveyed
Definite value 90.28%w/w).By thin-film distillation purified product, 410kg 4- ((2- ethyoxyl -2- oxoethyls) (methoxies are produced
Base carbonyl) amino) ethyl butyrate, purity (passing through GC) (yield of measured value and 98.77%A with 96.59%w/w
76%).
Example 4：
Repeat the program reported in example 3, there is provided 400kg 4- ((2- ethyoxyl -2- oxoethyls) (methoxycarbonyl)
Amino) ethyl butyrate, the purity (passing through GC) (yield 70%) of measured value and 98.04%A with 97.55%w/w.
Example 5：
Synthesize (the 2H)-dimethyl dicarboxylate (compound VI) of 5- hydroxyl -3,6- dihydropyridines -1,4.
By reactor equipped with 4- ((2- ethyoxyl -2- oxoethyls) (methoxycarbonyl) amino) ethyl butyrate (384kg,
Measured value is 92.55%w/w) and methanol (3489kg).Solution is heated to T=40 DEG C -45 DEG C, and added and leads in 1 hour
Cross the solution for being mixed with methanol 30% sodium methoxide (27kg) and methanol (152kg).By mixture at T=40 DEG C -45
Kept under agitation at DEG C 8 hours.Glacial acetic acid (11kg) is added, and gained mixture is passed through into distillation and concentration to residue.Will
The residue is diluted with toluene (1670kg).Other 410kg solvent is removed by being evaporated under reduced pressure.30% in methanol is added
After sodium methoxide (760kg), heat the mixture to backflow and continue 5 hours.By distillation and concentration mixture, 960kg solvents are removed,
And then it is diluted with toluene (768kg) again, and temperature is set as T=50 DEG C -55 DEG C.Keeping the temperature at 10
DEG C and 20 DEG C between while, the toluene mixture is transferred to equipped with water (1920kg), glacial acetic acid (384kg) and sodium chloride
In the second reactor of (96kg).The amount (96kg) of the toluene used in washing is collected in the second reactor.By temperature
It is set as T=30 DEG C -40 DEG C and separate aqueous layer.Organic layer is used what is prepared by mixing water (960kg) and sodium chloride (64kg)
Solution and then washed with water (384kg).By the organic solution of distillation and concentration under atmospheric pressure, 622kg toluene is produced
In 5- hydroxyls -3,6- dihydropyridine-Isosorbide-5-Nitrae (2H)-dimethyl dicarboxylate (measured value 38.31%w/w, yield 86%).
Example 6：
The method described in example 5 is repeated, from 410kg 4- ((2- ethyoxyl -2- oxoethyls) (methoxycarbonyl) ammonia
Base) ethyl butyrate (measured value 96.59%w/w) start and obtain the 5- hydroxyl -3,6- dihydropyridines in 868kg toluene -
Isosorbide-5-Nitrae (2H)-dimethyl dicarboxylate (measured value 26.26%w/w, yield 74%).
Example 7：
Synthesize 1,4- dioxa -7- azaspiros [4.5] decane -7,10- dimethyl dicarboxylates (compound VII).
By (the 2H)-dimethyl dicarboxylate 32.2%w/w in toluene of 5- hydroxyl -3,6- dihydropyridines -1,4 solution
(434kg) is fitted into reactor.Make the solution be anhydrous by azeotropic distillation, and then add toluene to be amounted to
734kg solution.Add ethylene glycol (86kg) and heat the mixture to backflow, and 50kg solvents are removed by distillation.So
Added the mixing prepared by mixing anhydrous methanesulfonic acid (3.7kg) and ethylene glycol (30kg) into the solution in 1.5 hours afterwards
Thing.Mixture is maintained the reflux for 3 hours, while solvent distillation and replaces it with same amount of toluene.Added in 35 minutes another
The anhydrous methanesulfonic acid (5kg) and ethylene glycol (18kg) of outer amount, and carry out distillation and continue other 4 hours, replace passing through with toluene
The solvent being distilled off.Then mixture is cooled to T=30 DEG C -40 DEG C and with potassium carbonate (4kg), ADSP
The processing of (2kg) and water (140L), and pH is adjusted to 7-8 units.Mixture is concentrated, is removed by distillation under atmospheric pressure
435kg solvents.Mixture is diluted with toluene (244kg) and water (56kg).Other 285kg is removed by distillation under atmospheric pressure
Solvent.Mixture toluene (183kg) is diluted and is cooled to T=50 DEG C -60 DEG C.Layer is separated.By water layer in T=50
Extracted at DEG C -60 DEG C with toluene (163kg).Organic layer is collected and under atmospheric pressure by distillation and concentration, produce 391kg work
For 1,4- dioxa -7- azaspiros [4.5] decane -7,10- dimethyl dicarboxylates of toluene solution.
Example 8：
Repeat the preparation reported in example 7, there is provided the 339kg Isosorbide-5-Nitrae as toluene solution-dioxa -7- azaspiros
[4.5] decane -7,10- dimethyl dicarboxylates.
Example 9：
Synthesize 10- (Hydroxycarboamoyl) -1,4- dioxa -7- azaspiros [4.5] decane -7- carboxylate methyl ester (chemical combination
Thing VIII).
The solution obtained in the solution (391kg) and 241kg examples 8 that are obtained in example 7 is merged.Will by being evaporated under reduced pressure
Mixture is concentrated into residue.The residue methanol (570kg) is diluted and is cooled to T=15 DEG C -20 DEG C.By hydroxylamine hydrochloride
(120kg) is fitted into reactor.In methanol 30% sodium methoxide (624kg) was added in 3.5 hours, maintains the temperature at T=15
In the range of DEG C -25 DEG C.Mixture is further stirred 12 hours at T=20 DEG C, and is subsequently cooled to T=0 DEG C -5 DEG C.
Hydrogen chloride (73kg) is blasted in mixture until pH is in the range of 5-7 units.Load acetone (100kg), and will have low
Kept under agitation 2 hours at T=10 DEG C -15 DEG C in 5 pH mixture.Will with methanol 30% sodium methoxide (45kg)
PH is adjusted to 6-7, and suspension is cooled into T=0 DEG C -5 DEG C.Salt is removed by filtration and is washed with methanol (160kg).Pass through
780kg solvents are distilled under reduced pressure to concentrate filtrate, and keeping temperature is less than 40 DEG C.Then it is mixture is dilute with n-butanol (54kg)
Release and further remove 530kg solvents by distilling to concentrate.Residue is used into ethyl acetate at T=35 DEG C -40 DEG C
The mixture of (1056kg) and methanol (12kg) dilutes.Mixture is concentrated by distilling 780kg solvents under reduced pressure.By remnants
Thing is diluted with ethyl acetate (600kg).Other 590kg solvent is removed by being evaporated under reduced pressure.By residue ethyl acetate
(750kg) dilutes and kept for 90 minutes at T=35 DEG C -40 DEG C.Suspension was cooled to T=0 DEG C -5 DEG C in 2.5 hours,
And kept for 2 hours at the same temperature.Product is isolated by filtration, washed with ethyl acetate and at T=35 DEG C -40 DEG C
Decompression is lower to be dried 32 hours, produces 271.3kg 10- (Hydroxycarboamoyl)-Isosorbide-5-Nitrae-dioxa -7- azaspiro [4.5] last of the ten Heavenly stems
Alkane -7- carboxylate methyl esters (measured value 87.7%w/w, purity 98.8%A).From (2H)-two of 5- hydroxyl -3,6- dihydropyridines -1,4
The gross production rate of carboxylic acid dimethyl ester is 93%.
Claims (27)
1. a kind of method for being used to manufacture the compound with lower Formula IV,
Both wherein R1 and R2 are methyl or ethyl, be the described method comprises the following steps：
A) compound with Formulas I is made,
Reacted with anhydrous acid and methanol or ethanol, to obtain the compound with Formula II,
Wherein when applying methanol in the reaction, R2 is methyl, and when applying ethanol in the reaction, R2 is ethyl.
2. according to the method for claim 1, wherein the anhydrous acid is anhydrous methanesulfonic acid.
3. according to the method for claim 2, wherein the compound with Formula II obtains as the mesylate for being portrayed as Formula II b
Wherein when applying methanol in the reaction, R2 is methyl, and when applying ethanol in the reaction, R2 is ethyl.
4. according to the method for claim 3, wherein the compound with Formula II b is obtained by one-pot synthesis.
5. according to the method any one of claim 1-4, the step of methods described is included additionally below：
B) make this that there is Formula II or IIb compound
Reacted with alkali and glyoxalic acid methylester or glyoxylic acid ethyl ester, to obtain the compound with formula III,
C) compound with formula III is changed into the compound with formula IV by hydrogenating
D) make that there is the compound of formula IV to be reacted with methylchloroformate or ethyl chloroformate, to obtain the chemical combination with Formula V
Thing
Wherein when applying methylchloroformate in the reaction, R1 is methyl, or ought apply ethyl chloroformate in the reaction
When, R1 is ethyl, and
Wherein when applying methanol in the reaction, R2 is methyl, or when applying ethanol in the reaction, R2 is ethyl,
And
Wherein when applying glyoxalic acid methylester in the reaction, R3 is methyl, or ought apply glyoxylic acid ethyl ester in the reaction
When, R3 is ethyl.
6. according to the method for claim 5, wherein step a), b), c) and d) carried out in toluene.
7. a kind of method for being used to manufacture the compound with lower Formula IV,
Both wherein R1 and R2 are methyl or ethyl, be the described method comprises the following steps：
B) make that there is Formula II or IIb compound
Reacted with alkali and glyoxalic acid methylester or glyoxylic acid ethyl ester, to obtain the compound with formula III,
C) compound with formula III is changed into the compound with formula IV by hydrogenating
D) make that there is the compound of formula IV to be reacted with methylchloroformate or ethyl chloroformate, there is the change of Formula V to obtain this
Compound
Wherein when applying methylchloroformate in the reaction, R1 is methyl, or ought apply ethyl chloroformate in the reaction
When, R1 is ethyl, and
Wherein R2 independently represents methyl or ethyl, and
Wherein when applying glyoxalic acid methylester in the reaction, R3 is methyl, or ought apply glyoxylic acid ethyl ester in the reaction
When, R3 is ethyl.
8. according to the method for claim 7, wherein step b), c) and d) carried out in toluene.
9. according to the method any one of claim 5-8, wherein the alkali used in step b) is triethylamine.
10. according to the method any one of claim 5-9, wherein the compound with Formula V is by using acidifying water washing
Or purified by distillation or by the combination of both purification strategies.
11. according to the method any one of claim 5-10, wherein the compound with Formula V is pure by thin-film distillation
Change.
12. according to the method any one of claim 1-11, the step of methods described is included additionally below：
E) should the compound with Formula V
Reacted with the caustic alcohol in the sodium methoxide or ethanol in methanol, to obtain the compound with Formula IV,
R1, R2 and R3 of the wherein compound with Formula V independently represent methyl or ethyl, and
When applying the sodium methoxide in methanol in the reaction, both the R1 and R2 of the compound with Formula IV are methyl, or
For person when applying the caustic alcohol in ethanol in the reaction, both the R1 and R2 of the compound with Formula IV are ethyl.
13. a kind of method for being used to manufacture the compound with lower Formula IV,
It the described method comprises the following steps：
E) compound with Formula V is made
Reacted with the caustic alcohol in the sodium methoxide or ethanol in methanol, to obtain the compound with Formula IV,
R1, R2 and R3 of the wherein compound with Formula V independently represent methyl or ethyl, and wherein
When applying the sodium methoxide in methanol in the reaction, both the R1 and R2 of the compound with Formula IV are methyl, or
For person when applying the caustic alcohol in ethanol in the reaction, both the R1 and R2 of the compound with Formula IV are ethyl.
14. according to the method any one of claim 12-13, wherein step e) is carried out in toluene, preferably 2-6 volumes
Toluene, such as the toluene of the toluene of 3-5 volumes, e.g., from about 4 volumes.
15. according to the method any one of claim 12-14, the reaction in wherein step e) is between 70 DEG C and 85 DEG C
At a temperature of carry out.
16. according to the method any one of claim 12-15, the reaction in wherein step e) is entered at a reflux temperature
OK.
17. a kind of method for being used to manufacture the compound with Formula IV, methods described are included according to any in claim 1-16
All step a), b), c), d) and e) described in.
18. according to the method any one of claim 1-17, wherein the compound with Formula IV is subsequently converted to have
There is the compound of Formula IX,
It is Gaboxadol that this, which has the compound of Formula IX,.
19. a kind of method for manufacturing Gaboxadol, wherein compound VI are the intermediates of methods described, and wherein described
Compound VI is manufactured by the method according to any one of claim 1-17.
20. a kind of method for manufacturing Gaboxadol, methods described is included by according to any one of claim 1-17 institutes
Compound of the method manufacture with Formula IV stated, and Gaboxadol is then manufactured by the compound with Formula IV.
21. according to the method any one of claim 18-20, methods described includes wherein making the compound with Formula IV
The step of with glycol reaction to obtain the compound with Formula VII,
Both wherein R1 and R2 are methyl or ethyl.
22. according to the method any one of claim 18-21, methods described includes wherein making the chemical combination with Formula VII
The step of thing and azanol reaction are to obtain the compound with Formula VIII
Wherein R1 represents methyl or ethyl.
23. according to the method any one of claim 18-22, methods described is included wherein by the chemical combination with Formula VIII
Thing is converted into the step of compound with Formula IX,
It is Gaboxadol that this, which has the compound of Formula IX,.
24. the compound with lower Formula IV,
Both wherein R1 and R2 are methyl or ethyl, and the compound passes through the method according to any one of claim 1-17
Obtain.
25. the compound with Formula IX,
The compound is Gaboxadol, is obtained by the method according to any one of claim 1-23.
26. a kind of compound with Formula V,
Wherein R1, R2 and R3 are entirely methyl.
27. a kind of compound with Formula II b,
Wherein R2 is methyl or ethyl.
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| DKPA201500181 | 2015-03-24 | ||
| DKPA201500181 | 2015-03-24 | ||
| PCT/EP2016/056244 WO2016150953A1 (en) | 2015-03-24 | 2016-03-22 | Manufacture of 4,5,6,7-tetrahydroisozaxolo[5,4-c]pyridin-3-ol |
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| WO2019110371A1 (en) * | 2017-12-05 | 2019-06-13 | Basf Se | Organic sulfonic acid salts of amino acid esters and process for their preparation |
| CA3120856A1 (en) | 2018-11-21 | 2020-05-28 | Certego Therapeutics, Inc. | Gaboxadol for reducing risk of suicide and rapid relief of depression |
| CN113286780A (en) * | 2019-01-08 | 2021-08-20 | 巴斯夫欧洲公司 | Process for preparing organic sulfates of amino acid esters |
| WO2021236876A2 (en) | 2020-05-20 | 2021-11-25 | Certego Therapeutics Inc. | Ring deuterated gaboxadol and its use for the treatment of psychiatric disorders |
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| EP0000167A1 (en) * | 1977-06-20 | 1979-01-10 | Povl Krogsgaard-Larsen | 1,2,3,6-Tetrahydroisonicotinic acid and derivatives thereof, methods and starting products for their preparation, and pharmaceutical compositions containing them. |
| CN101679318A (en) * | 2007-04-05 | 2010-03-24 | 美国西门子医疗解决公司 | Development of molecular imaging probes for carbonic anhydrase-IX using click chemistry |
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| IL89351A0 (en) | 1988-03-14 | 1989-09-10 | Lundbeck & Co As H | 4,5,6,7-tetrahydroisothiazolo(4,5-c)pyridines,process for their preparation and pharmaceutical compositions containing them |
| DE19525598C2 (en) | 1995-07-13 | 1997-09-25 | Max Planck Gesellschaft | sleeping pills |
| ES2341004T3 (en) | 2003-06-25 | 2010-06-14 | H. Lundbeck A/S | GABOXADOL TO TREAT DEPRESSION AND OTHER AFFECTIVE DISORDERS. |
| AR045540A1 (en) | 2003-09-05 | 2005-11-02 | Lundbeck & Co As H | METHOD OF ELABORATION OF 4,5,6,7 TETRAHYDROISOXAZOL [5,4-C] PIRIDIN-3-OL (THIP) |
| WO2016150953A1 (en) | 2015-03-24 | 2016-09-29 | H. Lundbeck A/S | Manufacture of 4,5,6,7-tetrahydroisozaxolo[5,4-c]pyridin-3-ol |
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| PL3274331T3 (en) | 2020-06-15 |
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| LT3274331T (en) | 2020-04-10 |
| DK3274331T3 (en) | 2020-03-23 |
| EP3274331A1 (en) | 2018-01-31 |
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| MA41802B1 (en) | 2020-04-30 |
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| AU2016236239A1 (en) | 2017-08-31 |
| ME03673B (en) | 2020-10-20 |
| EP3274331B1 (en) | 2020-02-26 |
| KR20170129778A (en) | 2017-11-27 |
| HK1248689A1 (en) | 2018-10-19 |
| KR102363715B1 (en) | 2022-02-15 |
| WO2016150953A1 (en) | 2016-09-29 |
| CA2977437C (en) | 2023-07-04 |
| RS60063B1 (en) | 2020-04-30 |
| US20200223865A1 (en) | 2020-07-16 |
| US11332478B2 (en) | 2022-05-17 |
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| HUE048370T2 (en) | 2020-07-28 |
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